Olanzapine counteracts stress-induced anxiety-like behavior in rats
Olanzapine counteracts stress-induced anxiety-like behavior in rats
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奥氮平可以抵消大鼠应激引起的焦虑样行为
DOI：
10.1016/j.neulet.2008.04.017
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发表时间：
2008
影响因子：
2.5
通讯作者：
R. Rimondini
中科院分区：
文献类型：
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作者：
F. Locchi;R. Dall'olio;O. Gandolfi;R. Rimondini
据报道，非典型抗精神病药（例如奥氮平）具有抗焦虑特性，多项临床前和临床研究表明。此外，一些实验证据表明，奥氮平可以减少激活的焦虑样行为测试（例如盖勒-塞夫特测试、超声波发声测试和压力诱导的乙醇消耗）中的恐惧和焦虑。在此，我们假设奥氮平的抗焦虑作用可能是通过 3α-羟基-5α-pregnan-20-one [allopregnanolone (ALLO)] 间接激活 γ-氨基丁酸 (GABA) 能系统所致，3α-羟基-5α-pregnan-20-one [allopregnanolone (ALLO)] 是一种有效的神经活性类固醇，可正向调节 A 型苯二氮卓类药物 - γ-氨基丁酸 (GABAA)/苯二氮卓类受体复杂。为了解决这个问题，我们使用临床前动物试验来筛选新型抗焦虑化合物——高架十字迷宫（EPM）——在基础条件下和急性或重复（21天）奥氮平（0.5mg/kg，腹腔注射）给药后45分钟抑制应激后。因此，在这种情况下，我们研究了 5-α-还原酶抑制剂非那雄胺 (FIN) (50mg/kg) 与奥氮平共同给药后的效果。 FIN 是一种类固醇生成酶抑制剂，通过抑制 II 型 5-α 还原酶发挥作用，这种酶可转化为 5-α 还原代谢物，如 GABAA 阳性神经活性类固醇 ALLO。结果显示，奥氮平的急性治疗仅对应激大鼠有抗焦虑作用，但慢性治疗则无抗焦虑作用。与 FIN 联合给药可以抵消这种抗焦虑作用。这些证据表明奥氮平的抗焦虑作用可能是由于奥氮平可能通过激活 GABA 系统对类固醇功能产生作用。
Atypical antipsychotics, such as olanzapine, have been reported to display anxiolytic properties as shown in several preclinical and clinical studies. Furthermore, several experimental evidences have shown that olanzapine reduces fear and anxiety in activated anxiety-like behavior test such as Geller-Seifter test, ultrasonic vocalization test and stress-induced EtOH consumption. Here, we hypothesized that the anxiolytic action of olanzapine might be due to via an indirect activation of the γ-amino butyric acid (GABA)-ergic system through 3α-hydroxy-5α-pregnan-20-one [allopregnanolone (ALLO)], a potent neuroactive steroid that positively modulates the benzodiazepine-γ-aminobutyric acid type A (GABAA)/benzodiazepine receptors complex. To address this question, we used a preclinical animal test to screen for novel anxiolytic compounds – the elevated plus-maze (EPM) – in basal condition and after 45 min restrain stress after acute or repeated (21 days) administration of olanzapine (0.5mg/kg, i.p.). In this condition, we therefore study the effect of the 5-alpha-reductase inhibitor finasteride (FIN) (50mg/kg) after co-administration with olanzapine. FIN is an inhibitor of steroidogenic enzymes which acts by inhibiting type II 5-alpha reductase, the enzyme that converts into 5-alpha-reduced metabolites like the GABAApositive neuroactive steroid ALLO. Results showed an anxiolytic effect of the acute, but not of the chronic, treatment with olanzapine only in stressed rats. This anxiolytic effect was counteracted by the co-administration with FIN. These evidences suggest that the anxiolytic effects of olanzapine might be due to possible action of olanzapine on steroid function via activation of GABA system.
药物挑战揭示了偏好酒精的 P 大鼠在自愿饮酒的应激促进和戒断诱发的焦虑之间的调节差异。
DOI：
10.1111/j.1530-0277.2007.00445.x
发表时间：
2007
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Overstreet,DavidH;Knapp,DarinJ;Breese,GeorgeR
通讯作者：
Breese,GeorgeR